Maternal Folic Acid and Dietary Folate Intake in Relation to Sex Ratio at Birth and Sex-Specific Birth Weight in China.

BACKGROUND: It is well-established that prenatal folic acid supplements can reduce neural tube defects. However, the associations between folic acid supplementation, dietary folate intake, and overall folate intake with sex-specific birth outcomes are not yet fully understood. OBJECTIVES: This study aims to investigate the association of periconceptional folic acid supplement, dietary folate, and total folate intake with the sex ratio at birth and sex-specific birth weight. METHODS: Data were sourced from a cross-sectional survey conducted between August and December 2013 in Northwest China, involving 7318 infants and their mothers, recruited using a stratified multistage random sampling method. Folic acid supplements (400 µg/d) were ascertained via a retrospective in-person interview. Dietary folate was evaluated using a validated food frequency questionnaire. Birth outcomes, including sex and weight at birth, were obtained from the Medical Certificate of Birth. Generalized linear models were employed to calculate relative risks (RRs) or differences with 95% confidence intervals (CIs). RESULTS: No association or dose-response relationship was observed between folic acid supplement, dietary folate, and total folate intake during periconception and the likelihood of male births. However, women who took folic acid supplements during pre- and post-conception were associated with an increased male birth weight by 52.8 (8.1 to 97.5) g. Additionally, the total folate intake during periconception was associated with birth weight for males (upper vs. lower tertile: ß = 38.8, 95%CI: 5.0 to 72.5 g, p-trend = 0.024) and females (upper vs. lower tertile: ß = 42.4, 95%CI: 6.7 to 78.1; p-trend = 0.022). CONCLUSIONS: Our findings indicate that periconceptional total folate intake does not correlate with sex ratio at birth but was positively linked to infant birth weights, regardless of gender. These findings offer novel insights into potential benefits of total folate intake, beyond the prevention of neural tube defects, for policymakers and public health.

Causal relationship between folic acid and prostate cancer risk: Insights from Mendelian randomization analysis.

OBJECTIVE: Folic acid is a commonly used dietary supplement of trace element, but it may increase the risk of prostate cancer (PCa). The aim of this study was to investigate the causal relationship between PCa and folic acid supplementation, as well as dietary folate equivalents, using Mendelian randomization (MR) analysis. METHODS: The Genome-Wide Association Study (GWAS) data of folic acid supplementation and dietary folate equivalents were selected from UK Biobank. Meta-analysis of GWASs of PCa was obtained from PCa Association Group to Investigate Cancer-Associated Alterations in the Genome consortium. MR analysis was performed with inverse variance weighted (IVW) method, MR-Egger regression, simple mode, weighted median, and weighted mode analysis. Heterogeneity and horizontal pleiotropy tests and reverse MR analysis were conducted to assess the robustness and reliability of the causal inference. RESULTS: Six single nucleotide polymorphisms (SNPs) associated with folic acid supplementation and five SNPs associated with dietary folate equivalents were identified as instrumental variables. Genetically predicted folic acid supplementation was associated with an increased risk of PCa (OR 1.200, p < 0.001, by IVW method), and there was no evidence of heterogeneity, horizontal pleiotropy, or significant reverse causality (all p > 0.05). In contrast, dietary folate equivalents showed no significant correlation with PCa (p > 0.05 for all five MR methods). CONCLUSION: This study demonstrated an association between increased risk of PCa and folic acid supplementation, but not with dietary folate equivalents. These findings have implications for public health interventions and personalized preventive strategies for PCa.

The association between dietary folate intake and risk of colorectal cancer incidence: A systematic review and dose‒response meta-analysis of cohort studies.

Background: Dietary components can influence the incidence of colorectal cancer (CRC). Folate is one of the compounds that plays an essential role in the formation of DNA structures, which can lead to or prevent tumorigenesis. The present study is the first systematic review and dose-response meta-analysis of cohort studies evaluating the association between dietary folate intake and the risk of CRC. Methods: The PubMed/Medline, Scopus, and ISI Web of Science databases were systematically searched for cohort studies that assessed the association between folate intake and CRC up to January 2024. Summary relative risks (RRs) and 95 % confidence intervals (CIs) were calculated using a random effects model. Also, linear and nonlinear dose-response analyses were conducted for the dose-response associations between folate intake and risk of CRC. Results: Eighteen prospective cohort studies with 931,469 participants, 14,860 CRC patients, 3536 colon cancer (CC) patients, and 1075 rectal cancer (RC) patients were included in the analysis. The summary RR of CRC for each 100-µg increase in dietary folate intake was 0.97 (95 % CI: 0.95-0.99, I2: 0.0 %, P-heterogeneity: 0.616), which can be related to BMI (0.97 (95 % CI: 0.95-0.99)); a more protective effect was also observed in subjects who drank alcohol (0.97 (95 % CI: 0.95-0.99)) and those who smoked (0.97 (95 % CI: 0.95-0.99)). Additionally, it was positively related to a 7 % lower risk of CC (0.93 (95 % CI: 0.87-0.99, I2: 33.7 %, P-heterogeneity: 0.159)), and the null relation for RC was 0.98 (95 % CI: 0.90-1.08), I2: 16.6 %, P-heterogeneity: 0.309). There was evidence of nonlinearity in which up to 500 µg/day dietary folate intake was inversely associated with CC (P nonlinearity = 0.04). Conclusion: The findings showed an inverse association between dietary folate intake and the risk of CRC, especially in high-risk persons, those who have a higher BMI, alcohol drinkers, and smokers.

Folate in the United States Population and its Association with Congestive Heart Failure.

Background: To investigate the relationship between red blood cell (RBC) folate and congestive heart failure (CHF). Methods: We extracted the concentrations of RBC folate and collated CHF information from the National Health and Nutrition Examination Survey (NHANES) survey (12820 individuals). Weighted univariate logistic regression, weighted multivariate logistic regression, and restrictive cubic spline (RCS) were used to assess the relationship between RBC folate concentrations and CHF. Results: The unadjusted model showed that the highest tertile group of RBC folate concentration was significantly associated with a higher risk of CHF compared to the lowest tertile group of RBC folate levels (odds ratio [OR] = 3.09; 95% confidence interval [CI], 2.14-4.46). Similar trends were seen in the multivariate-adjusted analysis (OR = 1.98; 95% CI: 1.27-3.09). The OR was > 1.0 when the predicted RBC folate exceeded 2757 nmol/L in the RCS model, indicating that the risk of CHF was low and relatively stable up to a predicted RBC folate level of 2757 nmol/L, but began to increase rapidly thereafter (p = 0.001). Conclusions: The risk of CHF may be increased either by high RBC folate concentrations (highest tertile of RBC folate or > 2637 nmol/L) or by folate deficiency. Considering the two sides of the association between RBC folate and CHF, there is a need for large-scale clinical research to better investigate if the association between RBC folate and CHF is a cause-effect relationship, what are the underlying pathophysiological basis, as well as to identify optimal dietary folate equivalent (DFE) and RBC folate concentration intervals.

Association between dietary folate intake and the risk of osteoporosis in adults: a cross-sectional study.

BACKGROUND: Increased intake of specific vitamins has been linked to a decreased prevalence of osteoporosis. However, the association between dietary folate intake and the risk of osteoporosis in the general population remains incompletely understood. Therefore, we aimed to determine the association between dietary folate intake and the risk of osteoporosis in the general population of the USA. METHODS: In this cross-sectional study, data from the National Health and Nutrition Examination Survey (2017-2020) were collected. Osteoporosis was considered to be indicated by a bone mineral density greater than 2.5 standard deviations below the mean of the young adult reference group. Dietary folate intake was measured by a 24-hour dietary recall. Multivariate logistic regression models and restricted cubic spline models were used. RESULTS: The study included 2297 participants (mean age: 63.69 ± 0.35 years), 49.92% of whom were female. In the general population, increased dietary folate intake was directly associated with a decreased risk of osteoporosis (P for trend = 0.005). In the age > 60 years and female subgroups, folate intake was inversely associated with the risk of osteoporosis (P for trend < 0.001). The dose‒response curve suggested that this association was nonlinear (P for nonlinearity = 0.015). CONCLUSIONS: Our cross-sectional study provides initial insights into the inverse association between dietary folate intake and the risk of osteoporosis in the general U.S. POPULATION: Further research is needed to confirm these associations.

The protective effect of dietary folate intake on gastric cancer is modified by alcohol consumption: A pooled analysis of the StoP Consortium.

Dietary folate intake has been identified as a potentially modifiable factor of gastric cancer (GC) risk, although the evidence is still inconsistent. We evaluate the association between dietary folate intake and the risk of GC as well as the potential modification effect of alcohol consumption. We pooled data for 2829 histologically confirmed GC cases and 8141 controls from 11 case-control studies from the international Stomach Cancer Pooling Consortium. Dietary folate intake was estimated using food frequency questionnaires. We used linear mixed models with random intercepts for each study to calculate adjusted odds ratios (OR) and 95% confidence interval (CI). Higher folate intake was associated with a lower risk of GC, although this association was not observed among participants who consumed >2.0 alcoholic drinks/day. The OR for the highest quartile of folate intake, compared with the lowest quartile, was 0.78 (95% CI, 0.67-0.90, P-trend = 0.0002). The OR per each quartile increment was 0.92 (95% CI, 0.87-0.96) and, per every 100 µg/day of folate intake, was 0.89 (95% CI, 0.84-0.95). There was a significant interaction between folate intake and alcohol consumption (P-interaction = 0.02). The lower risk of GC associated with higher folate intake was not observed in participants who consumed >2.0 drinks per day, ORQ4v Q1 = 1.15 (95% CI, 0.85-1.56), and the OR100 µg/day = 1.02 (95% CI, 0.92-1.15). Our study supports a beneficial effect of folate intake on GC risk, although the consumption of >2.0 alcoholic drinks/day counteracts this beneficial effect.

Association between dietary folate intake and severe abdominal aorta calcification in adults: A cross-sectional analysis of the national health and nutrition examination survey.

BACKGROUND: Prior studies have established a connection between folate intake and cardiovascular disease (CVD). Abdominal aortic calcification (AAC) has been introduced as a good predictor of CVD events, but no previous study has investigated the relationship between dietary folate intake and severe AAC. Therefore, the study aims to explore the association between dietary folate intake and severe AAC in the United States (US) middle-aged and elderly population. METHODS: This study employed cross-sectional data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to examine the relationship between dietary folate intake and severe AAC. Two 24-h dietary recall interviews were conducted to assess dietary folate intake and its sources, while a DXA scan was used to determine the AAC score. To analyze the association between dietary folate intake and severe AAC, a multivariable logistic regression model was applied, and a subgroup analysis was performed. RESULTS: Our analysis utilized data from 2640 participants aged 40 years and above, including 288 individuals diagnosed with severe AAC. After adjusting for confounding factors, we observed an inverted L-shaped association between folate intake and severe AAC. Upon further adjustment for specific confounding factors and covariates, the multivariable-adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the second, third, and fourth quartiles of folate intake, using the first quartile as the reference, were as follows: 1.24 (0.86-1.79), 0.86 (0.58-1.27), and 0.63 (0.41-0.97), respectively. Subgroup analysis results were consistent with the logistic regression models, indicating concordant findings. Moreover, no significant interaction was observed in the subgroup analyses. CONCLUSIONS: The study findings suggest an inverted L-shaped association between dietary folate intake and severe AAC. However, additional prospective investigations are necessary to explore the impact of dietary folate intake on severe AAC in patients.

Do Global Dietary Nutrient Datasets Associate with Human Biomarker Assessments? A Regression Analysis.

BACKGROUND: To assess the state and trends of global nutrition, our best tools are nationally representative assessments using human biomarker assays, yet these are expensive and logistically challenging. We instead often rely on more easily produced global nutrient datasets-measures of nutrients provided by the diet-as a proxy for nutritional intake and deficiency, due to their greater geographic and temporal coverage. However, the accuracy of global nutrient datasets is questionable. OBJECTIVE: We aimed to test whether estimates of inadequate dietary intake derived from existing global nutrient datasets reliably associate with biophysical deficiency. DESIGN: We performed linear regressions of estimates of inadequate dietary nutrient intake derived from three global nutrient datasets-Global Dietary Database, Global Nutrient Database, and Global Expanded Nutrient Supply (GENuS) model-against the existing suite of nationally representative biomarker survey data for three key nutrients of global concern in two vulnerable demographic groups: zinc, folate, and vitamin A in females of childbearing age; and zinc and vitamin A in children younger than 5 y. RESULTS: We found significant associations (P < 0.1) for only 3 of 22 regressions between global nutrition datasets and biophysical deficiency: zinc for females of childbearing age from GENuS and Global Dietary Database, and zinc for children under 5 y from GENuS. Folate and vitamin A show no reliable relationship between nutrient datasets and independent biomarker surveys. Applying the successful models for zinc to the accompanying full datasets yield estimates of global zinc deficiency of 31%-37% for these demographic groups. CONCLUSIONS: We found that few estimates of nutritional inadequacy from global dietary datasets are associated with more direct measures of biophysical deficiency from biomarker studies. Researchers and policymakers must be cautious when applying global nutrient datasets to questions of global health and use them for limited applications.

Association between dietary folate intake and bone mineral density in a diverse population: a cross-sectional study.

BACKGROUND: Osteoporosis is a major public health problem, yet the association between dietary folate intake and bone health has been rarely studied. This study aimed to investigate the relationship between dietary folate intake and bone mineral density (BMD) in the general population of the USA. METHODS: Utilizing data from the National Health and Nutrition Examination Survey, dietary folate intake was gauged through 24-h dietary recall and BMD was determined via dual-energy X-ray absorptiometry. Multivariate linear regression models and generalized additive models were employed for correlation analysis. RESULTS: The study incorporated 9839 participants (48.88% males, aged 20-85 years, mean age: 47.62 ± 16.22). The average dietary folate intake stood at 401.1 ± 207.9 µg/day. And the average total femur, femoral neck, trochanter, intertrochanter, and lumbar BMD were 0.98 ± 0.16 g/cm2, 0.84 ± 0.15 g/cm2, 0.73 ± 0.13 g/cm2, 1.16 ± 0.19 g/cm2, and 1.03 ± 0.15 g/cm2, respectively. The higher quartiles of dietary folate intake directly correlated with increased total femoral, femoral neck, intertrochanteric, and lumbar BMD (P for trend = 0.003, 0.016, < 0.001, and 0.033, respectively). A consistent positive association between folate intake and BMD across age groups was observed, with significant findings for individuals over 80 years and non-Hispanic whites. Physical activity level and serum 25-hydroxyvitamin D levels influenced the association, with an optimal daily folate intake of 528-569 µg recommended for postmenopausal women. CONCLUSION: In summary, our study reveals a significant positive association between dietary folate intake and BMD, across different age groups and particularly among individuals over 80 years old. Non-Hispanic whites benefit the most from increased folate intake. Physical activity level and serum 25-hydroxyvitamin D levels interact with this association. Screening and early intervention for osteoporosis may be essential for individuals with low dietary folate intake.

Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets.

Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.

Association of Folic Acid Supplementation, Dietary Folate Intake and Serum Folate Levels with Risk of Gestational Diabetes Mellitus: A Matched Case-Control Study.

Periconceptional folate supplementation is prevalent, raising concerns about possible side effects. The aim of this study was to investigate the associations of folic acid supplementation, dietary folate, serum folate with gestational diabetes mellitus (GDM) risk. In this matched case-control study, 81 pregnant women with GDM (cases) and 81 pregnant women with non-GDM (controls) were identified through age difference (≤3 y) and parity (Both primipara or multipara women) matching, and serum folate levels were measured during the GDM screening (24-28 gestational wk). Folic acid supplementation and dietary folate intake from three months prepregnancy through midpregnancy were assessed using a self-reported questionnaire and food frequency questionnaire. Multivariate binary logistic regression models were used to evaluate the association between folate and GDM. After adjusting for confounding factors, we observed that compared with folic acid supplementation dose ≤400 µg/d, pregnancies without folic acid supplementation and supplemental dose >800 µg/d were associated with GDM risk (adjusted odds ratio=7.25, 95% confidence interval: 1.34-39.36; adjusted odds ratio=4.20, 95% confidence interval: 1.03-17.22), while no significant association with a 400-800 µg/d dose of folic acid supplementation and GDM. Compared with folic acid supplementation dose ≤24 wk, pregnancies without folic acid supplementation were associated with GDM risk (adjusted odds ratio=6.70, 95% confidence interval: 1.22-36.77), while no significant association with folic acid supplementation dose >24 wk and GDM. No significant association of dietary folate and serum folate with GDM was found. No or a higher dose of folic acid supplementation would increase GDM risk and a dose of <800 µg/d is the safe dose.

Folate, vitamin B6, and vitamin B12 intakes are negatively associated with the prevalence of hypertension: A national population-based study.

We hypothesized that the prevalence of hypertension is related to B-vitamin intake in the general population, but it has not been sufficiently studied. This study aimed to investigate the intakes of dietary folate, vitamin B6, and vitamin B12 concerning hypertension in US adults. A total of 55 569 adults from National Health and Nutrition Examination Survey III and 1999-2014 were included in this study. Nutrient intake was collected from subjects through one or two 24-hour dietary reviews. Multiple logistic regression models were used to examine the relationship between these nutrient intakes and hypertension. Among male participants, dietary folate, vitamin B6, and vitamin B12 intakes were significantly and negatively associated with the prevalence of hypertension, with multivariate-adjusted odds ratios (ORs) of 0.61 (95% confidence interval [CI], 0.55-0.68), 0.65 (95% CI, 0.59-0.72), and 0.84 (95% CI, 0.75-0.95) for the highest quartile group compared with the lowest group. Results were similar for female participants, with multivariate-adjusted ORs of 0.63 (95% CI, 0.57-0.71), 0.60 (95% CI, 0.53-0.66), and 0.87 (95% CI, 0.77-0.98) for the highest quartile group. Moreover, there was a linear trend (Ptrend < .001) in both men and women that the prevalence of hypertension tended to decrease with increased intake of folate, vitamin B6, and vitamin B12; however, the decreases above the third quartile were negligible. Dietary folate, vitamin B6, and vitamin B12 were significantly associated negatively with hypertension, indicating that these nutrients might have a protective effect against hypertension in United States adults.

Maternal Folic Acid Supplementation, Dietary Folate Intake, and Low Birth Weight: A Birth Cohort Study.

Objectives: To investigate the independent and collective effects of maternal folic acid supplementation or dietary folate intake on the risk of low birth weight (LBW), and to further comprehensively examine the joint associations of folic acid supplementation and dietary folate intake with LBW by various clinical subtypes. Design: Participants were recruited from Gansu Provincial Maternity and Child Care Hospital. A standardized and structured questionnaire was distributed to collect demographic factors, reproductive and medical history, occupational and residential history, physical activity, and diet. Data on pregnancy-related complications and birth outcomes were extracted from medical records. Unconditional logistic regression models were used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for single and joint associations of folic acid supplementation and dietary folate intake with LBW. Setting: A birth cohort data analysis using the 2010-2012 Gansu Provincial Maternity and Child Care Hospital in Lanzhou, China. Participants: In total, 9,231 pregnant women and their children were enrolled in the study. Results: Compared with non-users, folic acid supplementation was associated with a reduced risk of LBW (OR: 0.80, 95% CI: 0.66-0.97), and the reduced risk was mainly seen for term-LBW (OR: 0.59, 95% CI: 0.41-0.85), and multiparous-LBW (OR: 0.72, 95% CI: 0.54-0.94). There were no significant associations between dietary folate intake and LBW, and there was no interaction between folic acid supplement and dietary folate intake on LBW. Conclusions: Our study results indicated that folic acid supplementation was associated with a reduced risk of LBW, and there was no interaction between folic acid supplements and dietary folate intake on LBW.

Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.

ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.

Dietary folate intake and fecundability in two preconception cohorts.

STUDY QUESTION: To what extent is dietary folate intake and total folate intake (dietary and supplemental intakes) associated with fecundability, the per cycle probability of conception? SUMMARY ANSWER: Preconception dietary folate intake was positively associated with fecundability in a monotonic pattern. WHAT IS KNOWN ALREADY: Supplemental folic acid has been associated with improved fertility, but little is known about the relation between dietary folate and fecundability. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 9559 women trying to conceive without fertility treatment and enrolled in the period 2013-2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used data from two internet-based prospective cohort studies of pregnancy planners from Denmark, where folic acid fortification is not performed (SnartForældre.dk (SF); n = 3755) and North America, where the food supply is fortified with folic acid (Pregnancy Study Online (PRESTO); n = 5804). Women contributed menstrual cycles at risk until they reported conception or experienced a censoring event. We used proportional probabilities regression models to compute fecundability ratios (FRs) and 95% CI, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with a dietary folate intake ≥400 µg/day, the adjusted FRs for women in SF were 0.92 (95% CI: 0.85-0.99) for intake 250-399 µg/day, and 0.80 (95% CI: 0.68-0.94) for intake of <250 µg/day. The corresponding FRs in PRESTO were 0.95 (95% CI: 0.89-1.01) and 0.81 (95% CI: 0.65-1.00). Compared with the highest level of total folate intake (diet folate ≥400 µg/day plus folic acid supplementation), in both cohorts fecundability was lowest among women with the lowest dietary intake <250 µg/day dietary folate and no supplementation (FR: 0.76, 95% CI: 0.59-0.98 [SF] and 0.49, 95% CI: 0.31-0.77 [PRESTO]). Further, total intake dietary folate <250 µg/day plus supplementation was associated with reduced fecundability for SF participants (FR; 0.79, 95% CI: 0.65-0.98) and for PRESTO participants (FR; 0.92, 95% CI: 0.72-1.16). LIMITATIONS, REASONS FOR CAUTION: It is unknown whether dietary folate and folic acid intake affect fecundability on its own or if there is an interaction with other micronutrients provided in healthy diet. Thus, the observed associations may not reflect dietary folate intake alone, but overall healthy diet. WIDER IMPLICATIONS OF THE FINDINGS: Recommendations for preconception dietary folate intake and folic acid supplementation are of importance not only to prevent neural tube defects but also to enhance fecundability. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the National Institute of Child Health and Human Development (R01-HD086742). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Does personalised nutrition advice based on apolipoprotein E and methylenetetrahydrofolate reductase genotype affect dietary behaviour?

Background: Dietary intake is linked to numerous modifiable risk factors of cardiovascular disease. Current dietary recommendations in the UK to reduce the risk of cardiovascular disease are not being met. A genotype-based personalised approach to dietary recommendations may motivate individuals to make positive changes in their dietary behaviour. Aim: To determine the effect of a personalised nutrition intervention, based on apolipoprotein E (ApoE, rs7412; rs429358) and methylenetetrahydrofolate reductase (MTHFR, rs1801133) genotype, on reported dietary intake of saturated fat and folate in participants informed of a risk genotype compared to those informed of non-risk genotype. Methods: Baseline data (n = 99) were collected to determine genotype (non-risk vs risk), dietary intake and cardiovascular risk (Q-Risk®2 cardiovascular risk calculator). Participants were provided with personalised nutrition advice via email based on their ApoE and MTHFR genotype and reported intake of folate and saturated fat. After 10 days, dietary intake data were reported for a second time. Results: Personalised nutrition advice led to favourable dietary changes, irrespective of genotype, in participants who were not meeting dietary recommendations at baseline for saturated fat (p < 0.001) and folate (p = 0.002). Only participants who were informed of a risk ApoE genotype met saturated fat recommendations following personalised nutrition advice. Conclusion: Incorporation of genotype-based personalised nutrition advice in a diet behaviour intervention may elicit favourable changes in dietary behaviour in participants informed of a risk genotype. Participants informed of a non-risk genotype also respond to personalised nutrition advice favourably but to a lesser extent.

[Influencing factors of insufficient and excessive folate intake in early pregnancy in Chengdu in 2017].

OBJECTIVE: To investigate the folate intake level of early pregnant women and its influencing factors in Chengdu. METHODS: The healthy singleton pregnant women with 8-14 weeks of pregnancy in an obstetrical clinic of maternal-and-child health care institution in Chengdu in 2017 were selected as the object of the study. The basic information of pregnant women was collected by questionnaire survey, and the dietary intake of all kinds of food in early pregnancy was collected by 3-day 24-hour dietary recall method, and the average daily intake of folate was calculated according to China Food Composition(2018). A self-designed questionnaire was used to collect the use of folic acid supplements in pregnant women in the past one month, and the average daily intake of folic acid supplements was calculated. According to the Chinese Dietary Reference Intakes(2013), the folate intake <600 µg DFE/d was defined as insufficient, and folic acid supplements intake ≥1000 µg/d was defined as excessive. The influencing factors of folate intake were analyzed by binary Logistic regression model. RESULTS: A total of 1579 valid samples were included. The average folate intake of early pregnant women in Chengdu was 865.8(778.6, 1461.0) µg DFE/d, the average dietary folate intake was 145.4(101.9, 200.7) µg/d, and the average folic acid supplements intake was 400.0(400.0, 800.0) µg/d. The rate of insufficient intake of folate in early pregnancy was 12.1%, and the rate of excessive intake of folic acid supplements was 13.0%. Compared with the primiparous group, the risk of insufficient folate intake was higher in the multiparous group(OR=1.708, 95%CI 1.175-2.482). Compared with the low income group, risk of insufficient folate intake in the medium and high income group was lower(OR=0.660, 95%CI 0.477-0.913); taking folic acid supplements before pregnancy has a lower risk of overdose of folic acid than the non-taking group(OR=0.594, 95%CI 0.423-0.835). CONCLUSION: The phenomenon of insufficient intake of total folate and excessive intake of folic acid supplements coexists among women in early pregnancy in Chengdu, and the rational use of folic acid supplements is worthy of attention.

Consumption of dietary folate estimates and its implication for reproductive outcome among women of reproductive age in Kersa: cross-sectional survey.

BACKGROUND: Dietary folate inadequacy is one the most common micronutrient deficiencies that cause neural tube defect (NTD) among infants in Sub-Saharan African countries. This study aims to determine the dietary intake of folate among women of reproductive age (WRA) of Kersa, Eastern Ethiopia. METHODS: A cross-sectional study took place among voluntary women that were selected from 1140 random households. Using a validated Food Frequency Questionnaire, participant's weekly dietary intake history of Ethiopian foods and dietary folate intake was worked out. Statistical analysis was done at a 95% confidence interval. Modified Poisson regression was used to identify factors associated with dietary folate consumption. RESULT: The estimated median usual intake of folate was 170 µg/d (IQR: 118.3; 252.2) and about 33% of WRA had low folate intake and 73.9% were at risk for folate inadequacy. From the reported food groups, Beans and Peas, Starchy staples, and Vitamin-A rich dark-green leafy vegetables were the top three ranked foods that contributed much of the dietary folate. The following conditions were statistically related to dietary folate inadequacy; women's age, being in poor wealth index, low dietary diversity, having seasonal employment, and reliance on market food sources. CONCLUSIONS: We found that women's dietary intake of folate in Kersa is very low and cannot protect their offspring from the risk of having NTD. They could also potentially be predisposed to poor health outcomes. Diversifying and fortification of Ethiopian wheats and salts could decrease the burden of folate deficiency in the country.

Ceramide synthase 6 mediates sex-specific metabolic response to dietary folic acid in mice.

Folic acid-fortified foods and multi-vitamin supplements containing folic acid (FA) are widely used around the world, but the exact mechanisms/metabolic effects of FA are not precisely identified. We have demonstrated that Ceramide Synthase 6 (CerS6) and C16:0-ceramide mediate response to folate stress in cultured cells. Here we investigated the dietary FA effects on mouse liver metabolome, with a specific focus on sphingolipids, CerS6 and C16:0-ceramide. Wild-type and CerS6-/- mice were fed FA-deficient, control, or FA over-supplemented diets for 4 weeks. After dietary treatment, liver concentrations of ceramides, sphingomyelins and hexosylceramides were measured by LC-MS/MS and complemented by untargeted metabolomic characterization of mouse livers. Our study shows that alterations in dietary FA elicit multiple sphingolipid responses mediated by CerS6 in mouse livers. Folic acid-deficient diet elevated C14:0-, C18:0- and C20:0- but not C16:0-ceramide in WT male and female mice. Additionally, FA over-supplementation increased multiple sphingomyelin species, including total sphingomyelins, in both sexes. Of note, concentrations of C14:0- and C16:0-ceramides and hexosylceramides were significantly higher in female livers than in male. The latter were increased by FD diet, with no difference between sexes in total pools of these sphingolipid classes. Untargeted liver metabolomic analysis concurred with the targeted measurements and showed broad effects of dietary FA and CerS6 status on multiple lipid classes including sex-specific effects on phosphatidylethanolamines and diacylglycerols. Our study demonstrates that both dietary FA and CerS6 status exhibit pleiotropic and sex-dependent effects on liver metabolism, including hepatic sphingolipids, diacylglycerols, long chain fatty acids, and phospholipids.

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction.

BACKGROUND: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. METHODS: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. RESULTS: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. CONCLUSIONS: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.